SUMMARY Lung cancer is the leading cause of cancer-related death worldwide, exceeding that attributable to breast, prostate, colon, kidney, and liver cancer combined. Recently, the identification of recurrent genetic alterations has led to molecularly-targeted therapies for a subset of lung cancers. Activating mutations in RAS-family oncoproteins are among the most frequent genomic alterations in non-small cell lung cancer (NSCLC) and are mutated in up to 30% of all human cancers. Despite intensive efforts to target KRAS, no molecularly targeted therapies exist and patients still receive cytotoxic and largely ineffective chemotherapies. Indeed, direct pharmacological inhibition of mutant RAS has remained difficult, and targeting of other downstream RAS effectors, in particular the MAPK pathway, has been ineffective due to toxicities and adaptive drug resistance mechanisms. In response to the urgent need for developing strategies to target KRAS mutant cancers, this Program Project has explored that action of agents that target the RAS network, producing insights into adaptive resistance mechanisms and characterizing the first direct KRAS mutant inhibitors. Our project, together with Rosen (RP2), established that the rebound in MAPK signaling occurring after MEK inhibition is responsible for adaptive drug resistance and, though a functional genomics screen, identified upstream activation of the FGFR1 signaling axis as contributing to this effect. Consequently, FGFR1 is an induced dependency produced by MEK inhibition and therapeutic approaches targeting MEK and FGFR1 are being developed as a clinical strategy for treating KRAS mutant lung cancers. Our renewal builds on these successes towards the goal of identifying additional combinatorial strategies targeting KRAS mutant cancers. Expanding upon extensive preliminary data, we study effectors required for tumor maintenance in KRAS driven lung cancers treated with MAPK or KRAS inhibitors, explore novel and existing strategies for combinatorial target inhibition, and examine the interplay between pathway inhibition, tissue and genomic context, and immune surveillance. The project builds on existing collaborations and incorporates innovative technology and mouse modeling systems into the program; it interacts with, and benefits from, each of the other projects and cores. Successful completion of the proposed work will provide critical insights into RAS signaling and form a foundation for bringing targeted therapy for KRAS mutant lung cancer into the clinical arena.